Prediction of Mitochondrial Protein Function by Comparative Physiology and Phylogenetic Profiling

The gap between the amount of genome information released by genome sequencing projects and our knowledge about the proteins' functions is rapidly increasing. To fill this gap, various ‘genomic-context’ methods have been proposed that exploit sequenced genomes to predict the functions of the encoded proteins. One class of methods, phylogenetic profiling, predicts protein function by correlating the phylogenetic distribution of genes with that of other genes or phenotypic characteristics. The functions of a number of proteins, including ones of medical relevance, have thus been predicted and subsequently confirmed experimentally. Additionally, various approaches to measure the similarity of phylogenetic profiles and to account for the phylogenetic bias in the data have been proposed. We review the successful applications of phylogenetic profiling and analyse the performance of various profile similarity measures with a set of one microsporidial and 25 fungal genomes. In the fungi, phylogenetic profiling yields high-confidence predictions for the highest and only the highest scoring gene pairs illustrating both the power and the limitations of the approach. Both practical examples and theoretical considerations suggest that in order to get a reliable and specific picture of a protein's function, results from phylogenetic profiling have to be combined with other sources of evidence.

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Sites Inferred by Metabolic Background Assertion Labeling (SIMBAL): adapting the Partial Phylogenetic Profiling algorithm to scan sequences for signatures that predict protein function

BMC Bioinformatics ◽

10.1186/1471-2105-11-52 ◽

2010 ◽

Vol 11 (1) ◽

Cited By ~ 9

Author(s):

Jeremy D Selengut ◽

Douglas B Rusch ◽

Daniel H Haft

Keyword(s):

Protein Function ◽

Predict Protein Function ◽

Phylogenetic Profiling

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Deacetylation by SIRT3 Relieves Inhibition of Mitochondrial Protein Function

Sirtuins ◽

10.1007/978-94-024-0962-8_5 ◽

2016 ◽

pp. 105-138 ◽

Cited By ~ 3

Author(s):

Peter Chhoy ◽

Kristin A. Anderson ◽

Kathleen A. Hershberger ◽

Frank K. Huynh ◽

Angelical S. Martin ◽

...

Keyword(s):

Protein Function ◽

Mitochondrial Protein

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Evolution and Cellular Function of Monothiol Glutaredoxins: Involvement in Iron-Sulphur Cluster Assembly

Comparative and Functional Genomics ◽

10.1002/cfg.406 ◽

2004 ◽

Vol 5 (4) ◽

pp. 328-341 ◽

Cited By ~ 38

Author(s):

Felipe Vilella ◽

Rui Alves ◽

María Teresa Rodríguez-Manzaneque ◽

Gemma Bellí ◽

Swarna Swaminathan ◽

...

Keyword(s):

Bacterial Species ◽

Mitochondrial Protein ◽

Protein Docking ◽

Physical Interaction ◽

Cluster Assembly ◽

Phylogenetic Profiles ◽

Eukaryotic Species ◽

Phylogenetic Profiling ◽

Two Hybrid

A number of bacterial species, mostly proteobacteria, possess monothiol glutaredoxins homologous to theSaccharomyces cerevisiaemitochondrial protein Grx5, which is involved in iron–sulphur cluster synthesis. Phylogenetic profiling is used to predict that bacterial monothiol glutaredoxins also participate in the iron–sulphur cluster (ISC) assembly machinery, because their phylogenetic profiles are similar to the profiles of the bacterial homologues of yeast ISC proteins. High evolutionary co-occurrence is observed between the Grx5 homologues and the homologues of the Yah1 ferredoxin, the scaffold proteins Isa1 and Isa2, the frataxin protein Yfh1 and the Nfu1 protein. This suggests that a specific functional interaction exists between these ISC machinery proteins. Physical interaction analyses using low-definition protein docking predict the formation of strong and specific complexes between Grx5 and several components of the yeast ISC machinery. Two-hybrid analysis has confirmed thein vivointeraction between Grx5 and Isa1. Sequence comparison techniques and cladistics indicate that the other two monothiol glutaredoxins ofS. cerevisiae, Grx3 and Grx4, have evolved from the fusion of a thioredoxin gene with a monothiol glutaredoxin gene early in the eukaryotic lineage, leading to differential functional specialization. While bacteria do not contain these chimaeric glutaredoxins, in many eukaryotic species Grx5 and Grx3/4-type monothiol glutaredoxins coexist in the cell.

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Abstract 144: Cardiac Expression of Mitochondrial Acetyltransferase Gcn5l1 Contributes to Ischemia-Reperfusion Injury and Alters Mitochondrial Energetics After Injury

Circulation Research ◽

10.1161/res.121.suppl_1.144 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Janet R Manning ◽

Dharendra Thapa ◽

Manling Zhang ◽

Michael W Stoner ◽

Iain Scott

Keyword(s):

Heart Failure ◽

Reperfusion Injury ◽

Protein Function ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Mitochondrial Protein ◽

Ischemic Heart ◽

Mitochondrial Proteins ◽

Ros Production ◽

Triphenyltetrazolium Chloride

Introduction: The increasing global burden of ischemic heart disease demands a closer examination of the mechanisms by which myocardial reperfusion produces injury to initiate long-term heart failure. Reactive oxygen species (ROS) generated after ischemia reperfusion (IR), in conjunction with the dysfunction of mitochondrial metabolic enzymes, have been identified as a primary mediator of cardiac reperfusion injury. The acetylation of mitochondrial proteins, regulated by opposing actions of NAD + -dependent sirtuin deacetylases and the recently identified mitochondrial acetyltransferase GCN5L1, has emerged as a key point of intersection between nutrient status and mitochondrial protein function in cardiomyoctyes. This makes the association between acetylation and ROS production an important topic of investigation. Intriguingly, global protein acetylation was recently reported to be upregulated in the hearts of human patients with ischemic heart failure. Despite this, it remains unknown whether GCN5L1 acetyltransferase activity plays a role in the regulation of metabolic proteins during IR injury. Hypothesis: Cardiac deletion of the acetyltransferase GCN5L1 reduces the acetylation of mitochondrial proteins during IR, reducing aberrant activity and preventing ROS production. Methods: Isolated work-performing hearts from cardiac-specific inducible GCN5L1 knockout mice were subjected to global ischemia and reperfusion. Contractility (+/- dP/dT) of the left ventricle was measured throughout as an index of post IR functional recovery. Tissue damage was assessed by measuring the release of lactate dehydrogenase and post-reperfusion staining of viable tissue with triphenyltetrazolium chloride. Acetylation levels of mitochondrial proteins were measured during IR using immunoblotting of homogenized hearts, which were also used to evaluate ROS production. Results and Conclusions: Mitochondrial acetylation was decreased in GCN5L1 hearts compared to WT, coinciding with improved post-IR recovery. We therefore conclude that acetylation of mitochondrial proteins by the acetyltransferase GCN5L1 is an important regulatory mechanism of IR-induced, ROS-mediated damage.

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Tissue-specific effects of leptin administration on the abundance of mitochondrial proteins during neonatal development

Journal of Endocrinology ◽

10.1677/joe.1.06251 ◽

2005 ◽

Vol 187 (1) ◽

pp. 81-88 ◽

Cited By ~ 4

Author(s):

M G Gnanalingham ◽

A Mostyn ◽

J Wang ◽

R Webb ◽

D H Keisler ◽

...

Keyword(s):

Protein Function ◽

Uncoupling Protein ◽

Mitochondrial Protein ◽

Anion Channel ◽

Later Life ◽

Mitochondrial Proteins ◽

Control Mechanisms ◽

Voltage Dependent Anion Channel ◽

Tissue Specific ◽

The Brain

Many tissues undergo a rapid transition after birth, accompanied by dramatic changes in mitochondrial protein function. In particular, uncoupling protein (UCP) abundance increases at birth in the lung and adipose tissue, to then gradually decline, an adaptation that is important in enabling normal tissue function. Leptin potentially mediates some of these changes and is known to promote the loss of UCP1 from brown fat but its effects on UCP2 and related mitochondrial proteins (i.e. voltage-dependent anion channel (VDAC) and cytochrome c) in other tissues are unknown. We therefore determined the effects of once-daily jugular venous administration of ovine recombinant leptin on mitochondrial protein abundance as determined by immunoblotting in tissues that do (i.e. the brain and pancreas) and do not (i.e. liver and skeletal muscle) express UCP2. Eight pairs of 1-day-old lambs received either 100 μg leptin or vehicle daily for 6 days, before tissue sampling on day 7. Administration of leptin diminished UCP2 abundance in the pancreas, but not the brain. Leptin administration had no affect on the abundance of VDAC or cytochrome c in any tissue examined. In leptin-administered animals, but not controls, UCP2 abundance in the pancreas was positively correlated with VDAC and cytochrome c content, and UCP2 abundance in the brain with colonic temperature. In conclusion, leptin administration to neonatal lambs causes a tissue-specific loss of UCP2 from the pancreas. These effects may be important in the regulation of neonatal tissue development and potentially for optimising metabolic control mechanisms in later life.

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